This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project I: Zondlo Helices are central biological recognition elements, interacting with proteins, DNA and RNA. The ability to mimic this secondary structure element predictably with a small molecule would allow control of myriad biological events. However, despite the ubiquity of helical recognition, few examples exist of small molecule mimics of helices. The primary theme of this work is the development of small molecule mimics of helices and their application to biological systems. In the process, we will examine the biological mechanisms of target recognition helics. Initial work will focus on mimicry of short recognition helices, proceeding to mimicry of extended s-helices. The acidic activation domains of the p53, p65 and VP16 proteins have been shown to interact with their target proteins through a short recognition helix, in which the primary interactions occur via hydrophobic residues at positions i, i+3 and i+4 (termed the FXXFF motif). We will prepare decalin-based scaffolds which allow presentation of the i, i+1, i+3 and i+4 residues (one face) of an helix. The scaffolds will be elaborated with appropriate side chains from the activation domain sequences. These molecules will be tested for binding to target proteins to assess scaffold suitability and effectiveness and for interaction specificity. Competition experiments with activation domain-derived peptides will determine that the same binding site is utilized. Mimics will be attached to DNA-binding domains to determine effectiveness in transcription activation. Additionally, the molecules will be attached to known small molecule DNA-binding motifs to generate cell-diffusible small molecule regulators of transcription.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017716-05
Application #
7381972
Study Section
Special Emphasis Panel (ZRR1-RI-A (03))
Project Start
2006-07-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$268,273
Indirect Cost
Name
University of Delaware
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Li, Linqing; Stiadle, Jeanna M; Levendoski, Elizabeth E et al. (2018) Biocompatibility of injectable resilin-based hydrogels. J Biomed Mater Res A 106:2229-2242
Drolen, Claire; Conklin, Eric; Hetterich, Stephen J et al. (2018) pH-Driven Mechanistic Switching from Electron Transfer to Energy Transfer between [Ru(bpy)3]2+ and Ferrocene Derivatives. J Am Chem Soc 140:10169-10178
Potocny, Andrea M; Riley, Rachel S; O'Sullivan, Rachel K et al. (2018) Photochemotherapeutic Properties of a Linear Tetrapyrrole Palladium(II) Complex displaying an Exceptionally High Phototoxicity Index. Inorg Chem 57:10608-10615
Potocny, Andrea M; Pistner, Allen J; Yap, Glenn P A et al. (2017) Electrochemical, Spectroscopic, and 1O2 Sensitization Characteristics of Synthetically Accessible Linear Tetrapyrrole Complexes of Palladium and Platinum. Inorg Chem 56:12703-12711
Li, Linqing; Stiadle, Jeanna M; Lau, Hang K et al. (2016) Tissue engineering-based therapeutic strategies for vocal fold repair and regeneration. Biomaterials 108:91-110
Li, Linqing; Mahara, Atsushi; Tong, Zhixiang et al. (2016) Recombinant Resilin-Based Bioelastomers for Regenerative Medicine Applications. Adv Healthc Mater 5:266-75
Suiter, Christopher L; Quinn, Caitlin M; Lu, Manman et al. (2015) MAS NMR of HIV-1 protein assemblies. J Magn Reson 253:10-22
Li, Linqing; Luo, Tianzhi; Kiick, Kristi L (2015) Temperature-triggered phase separation of a hydrophilic resilin-like polypeptide. Macromol Rapid Commun 36:90-5
Lau, Hang Kuen; Kiick, Kristi L (2015) Opportunities for multicomponent hybrid hydrogels in biomedical applications. Biomacromolecules 16:28-42
Mahadevaiah, Shruthi; Robinson, Karyn G; Kharkar, Prathamesh M et al. (2015) Decreasing matrix modulus of PEG hydrogels induces a vascular phenotype in human cord blood stem cells. Biomaterials 62:24-34

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